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Complete remission of cancer in late-stage disease by radiation and transfer of allogeneic MHC-matched immune T cells: lessons from GvL studies in animals

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Abstract

Most immunotherapy studies in animal tumor models are performed in early stages of the disease. Reports on the studies of treatment in late stages of tumor growth and metastasis are much rarer. To guide future efforts for treatment in late-stage disease, a model of effective immune rejection of advanced metastasized cancer is reviewed and lessons therefrom are summarized. Already cachectic DBA/2 mice with a subcutaneously transplanted syngeneic tumor (ESb-MP lymphoma) of 1.5 cm diameter and with macroscopic liver and kidney metastases at 4 weeks could be successfully treated by a combination of sublethal (5 Gy) irradiation followed by a single transfer of 20 million anti-tumor immune spleen cells from tumor-resistant allogeneic MHC-B10.D2 mice. Following intravenous cell transfer, the primary tumors became encapsulated and were eventually rejected from the skin while visceral metastases gradually disappeared leaving behind only scar tissue. There was wound-healing at the site of the rejected primary tumor, and the animals survived long term without any tumor recurrence. The complete eradication of late-stage disease by adoptive cellular immunotherapy could be corroborated noninvasively by 31P-NMR spectroscopy of primary tumors and by 1H-NMR microimaging of liver metastases. Conclusions from functional mechanistic studies in this model are summarized and clinical implications discussed.

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Abbreviations

ADI:

Adoptive cellular immunotherapy

allo-HSC:

Allogeneic hematopoietic stem cell

APC:

Professional antigen-presenting cell

BM:

Bone marrow

CD4:

Receptor for MHC class II

CD8:

Receptor for MHC class I

CD40:

Receptor for the co-stimulator CD154 (CD40L)

CMT:

Central memory T cell

CTL:

Cytotoxic T lymphocyte

CTLP:

Precursor of CTL

CXCR4:

Chemokine receptor for SDF-1

DC:

Dendritic cell

DLI:

Donor lymphocyte infusion

env:

Envelop gene

EMT:

Effector memory T cell

FDG:

Fluorescein-β-d-galactopyranoside

β-Gal:

β-galactosidase

mAb:

Monoclonal antibody

GOT:

Glutamate-oxaloacetate transaminase

GPT:

Glutamate-pyruvate transaminase

GvH:

Graft versus host

GvHD:

Graft-versus-host disease

GvL:

Graft-versus-leukemia effect

Gy:

Gray

H:

Histocompatibility

HLA:

Human leukocyte antigen

HvG:

Host versus graft

HSC:

Hematopoietic stem cell

IAP:

Intracisternal proviral A-type particle

iNOS:

Inducible nitric oxid synthase

Il-2Rβ, Il-7Ralpha:

Receptor chains for the cytokines Il-2 and Il-7

iPEC:

Immune peritoneal exudate cells

IFNR:

Type I interferon receptor

ISPL:

Immune spleen cells

i.v.:

Intravenous

i.p.:

Intraperitoneal

i.d.:

Intradermal

lacZ:

Gene coding for bacterial β-galactosidase

LTR:

Long terminal repeat DNA

mHA:

Minor histocompatibility antigen

Mls:

Minor lymphocyte stimulatory antigen

MHC:

Major histocompatibility complex

MMTV:

Mouse mammary tumor virus

MSC:

Mesenchymal stem cell

MTC:

Memory T cell

Mtv-7:

Gene coding for viral superantigen vSAG-7

NMR:

Nuclear magnetic resonance

NO:

Nitric oxide

NOD/SCID:

Non-obese-diabetes deficiency/severe combined immunodeficiency mouse strain

PEC:

Peritoneal exudate cells containing EMT

PME:

Phosphomonoesters

PT:

Primary tumor

SAG:

Superantigen

s.c.:

Subcutaneous

SDF-1:

Stromal-cell-derived factor 1 (CXCL12)

SMT:

Stem memory T cell

Sn:

Sialoadhesin

TAA:

Tumor-associated antigen

TIL:

Tumor-infiltrating lymphocyte

TCR:

Antigen-specific T-cell receptor

VCAM-1:

Vascular cell adhesion molecule 1

vSAG:

Viral superantigen

X-Gal:

Staining procedure to visualize β-gal expressing cells

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The author declares that no competing financial interests exist.

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Authors and Affiliations

  1. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Volker Schirrmacher

  2. IOZK Köln, Hohenstaufenring 30-32, Cologne, Germany

    Volker Schirrmacher

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Correspondence to Volker Schirrmacher.

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Schirrmacher, V. Complete remission of cancer in late-stage disease by radiation and transfer of allogeneic MHC-matched immune T cells: lessons from GvL studies in animals. Cancer Immunol Immunother 63, 535–543 (2014). https://doi.org/10.1007/s00262-014-1530-2

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  • DOI: https://doi.org/10.1007/s00262-014-1530-2

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